• 专利附录
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    • 专利摘要:
    Prostane derivatives of the formula <IMAGE> I wherein R1 is OR2 or NHR3; R2 is hydrogen, C1-10 alkyl, C4-10 cycloalkyl, C6-10 aryl, or a 5 or 6 membered heterocyclic ring having 1-3 hetero atoms selected from O, N and S; R3 is the residue of a hydrocarbon carboxylic or sulfonic acid of 1-15 carbon atoms; W is (a) an OH-substituted methylene group, (b) a <IMAGE> wherein the OH-groups in (a) or (b) can be in the alpha - or beta -position, or (c) such a group wherein the H atom of the OH group is replaced by the residue of a hydrocarbon carboxylic or sulfonic acid of 1-15 carbon atoms or by a conventional etherifying OH-blocking group; R4 is OH or hydroxy whose H atom is replaced as defined for W; and R5, R6, R7, R8, R9, R10 and R11 each independently is hydrogen or alkyl of 1-5 carbon atoms; or R9 and R10 together represent a direct bond; and, when R11 is alkyl, R10 can also be chlorine; and, for a derivative wherein R2 is hydrogen, the salts thereof with physiologically compatible bases, have improved prostaglandin activity.
    公开号:SU921465A3
    申请号:SU782636446
    申请日:1978-07-17
    公开日:1982-04-15
    发明作者:Скубалла Вернер；Радюхель Бернд；Шварц Норберт；Форбрюгген Хельмут；Мюллер Бернд；Маннесманн Герда；Логе Олаф；Шиллингер Эккехардт；Казальс-Штенцель Йорге
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    METHOD OF OBTAINING
    (54) The invention relates to a method of obtaining prostane derivatives not described in the literature of the general formula: or hydroxyl or acyloxy group with 1-4 carbon atoms; hydrogen or alkyl with 1-4 atoms and RT mami carbon, or RS and Re
    Derivative Derivations
    权利要求:
    Claims (4)
    [1]
    SALTS OR THEIR together represent a single bond, or in the case of RI a hydroxyl, and their salts having pharmacological activity. A method of producing alcohols is known, which consists in reducing the carbonyl compound with sodium borohydride fl. The purpose of the invention is the preparation of new pharmacologically active prostane derivatives of general formula I or their salts, based on the use of a known reaction. The goal is achieved by the method of obtaining prostane derivatives of general formula I or their salts, which consists in the fact that the compound of the general formula, x4 cioKj / Vz Bv CCNgS1 about h where R ,, Hj, RS, 84, PS, Re and R7 - have the above values are reduced with an alkali metal borohydride with a preliminary, if necessary, protective free hydroxyl tinder and the resulting compound is divided into epimers in any sequence, the protected hydroxy groups are released and / or the free hydroxyl groups are esterified, washed with ester modified carboxyl group or etherifying the carboxyl group, the carboxyl group is replaced by interaction with the compound of the general formula Rg N C O, where Rg is lower alkylsulfonyl or lower aipui, and if R is hydroxyl, the carboxyl group is converted into salt and the resulting gels known methods. 1P, the prostane derivatives of the general formula (D) or their salts have hypotensive and urinary effects. They also regulate abnormal heart rhythms and are inhibitors of platelet aggregation. ;. EXAMPLE 1 (IS. SR, 6R, 7B, 3R) -7-acetoxy-6- (E) - (38) -3-hydroxy-Loctene-6-ynyl - 3- (4-methoxycarbonyl -1 - butyl) - 2-bxabicyclo 3.3.0} octane. in 800 mg of a solution (IS, 5R, 6Я, 7R, 3R) -7-acetoxy-6- (E) -3-oxo-octo-6-ynyl-3 (4-methoxy-arobonyl-1 by-1) -2-occicycle 13.3 .0 octane in 24 ml of methanol and 10 ml of gdrofuran was added at -40 ° C in portions of 420 mg of sodium borohydride and stirred for 1 hour at -40 ° C. Then carefully mixed with 1 ml of glacial acetic acid, concentrated in vacuo , add methylene chloride to the precipitate, agitate the organic extract with 4% sodium bicarbonate solution, wash with water until neutral, dry the magnesium sulfate and evaporate in vacuo. After chromatography of the precipitate on silica gel with ether / pentane (6: 4), 250 mg of the corresponding compound are obtained (L configuration and 266 mg of the desired product as a white butter oil. The starting material for the target product is given as follows. 1-a) , (IS, 5R, 6R, 7R, SZ $) - 6: be4GZSH1Oksimyot1Y 3- (4-methoxycarbosh1l-1-butyl) -7- (tetragadro; - "shfan-2-ipoxy) -2-oxabicyclo. 3.3.0J octane. In a solution of 4.5 g (93, 11B) - (52) -9-hydroxy 14-oxa-15-phenyl-11- (tetrap1ropyran-2-yloxn) -16, 17, 18, 19, 20-pentanor-5 β-prostate methyl ester in 140 ml of tetrahydrofuran was added 3.8 g of mercury (II) acetate and stirred for 5 hours at room temperature in argon. Add 60 ml of 1N. caustic soda, stirred for 1 min, is added to a solution of 1.5 g of sodium borohydride in 60 mp 1N. caustic soda, stirred for 5 minutes, diluted with ether, shaken the brgaNic phase with water, dried with magnesium sulfate and evaporated in vacuo. After chromatography on silica gel, pentane / ether (8: 2) is obtained, 3.3 g of the expected product are obtained in the form of a white oil. sixteen). (18, 5R, 6R, 7R,. 3S) -6: benzyl-methyl-7-hydroxy-3- (4-methoxycarbonyl-1-butyl) -2-oxabitrate 3.3.0 octane and (IS, 5R, 6R, 7R, 3R) -6-benzo-1-hydroxymethyl-7-hydroxy-3- (4-methoxycarbonyl-1-butyl) -1 oxabicyclo 13.3.0 octane. 3.2 g of the compound obtained in Example 1a were stirred for 16 hours at room temperature with 80 ml of a mixture of glacial acetic acid, water and tetrafrandrofuran: (65/35/10), evaporated in vacuo and the residue was separated by silica gel chromatography. By using ether / pentane (7: 3), initially, 410 mg of compound 38-configuration, as well as in more pensive fractions, 1.65 g of compound 3g-configuration with d-chain of 4-methoxycarbonylbutyl in the form of white oil is obtained. 1c). (18, 5R, 6R, 7R, 3V) -7-acetoxy-6-benzyloxymethyl-3- (4-methoxycarboxy-1-1-butyl) -2-oxabicyclo | 3.3.0 octane. A solution of 1.5 g of ZK-etshmera (polar main product) prepared according to Example 16, 1 ml of acetic anhydride and 3 ml of Pyrdin was incubated for 16 hours at room temperature and then evaporated in vacuo to give 1.7 g of the desired product in vvde oil . 1d) (IS, 5R, 6R, 7R, WI). 7-acetoxy-6-hydroxymethyl-3- (4-methoxy 1 onyl-1-butnl) -2-oxabicyclo 3.3.0 oct. 4.8 g of the compound obtained in Example 1c for 3 hours are agitated in 200 ml of ethyl acetate and 50 ml of ethanol from 0.9 g of palladium (10% on carbon) in a hydrogen medium is filtered and evaporated in a vacuum, 3.7 g of the desired procedure are obtained. . in the form of white oil. 1e). (IS, 5R, 6R, 7R, 3R) -7-acetoxy-6-formyl-3- (4 methoxycarbonyl-1-butyl) -2-oxabicyclo 3.3.0 octane. To the solution (30 g of freshly obtained rocta Ks lens in 250 ml of abs. Methylene chloride), add a solution of 4 g of the compound obtained in Example 1 g in 120 ml of abs. methylene chloride, stirred for 30 minutes, mixed with 700 ml of ether and shaken four times with 40 ml of 10% sulfuric acid and four times with 40 ml of water. After drying over magnesium sulfate, it is evaporated in vacuo to give 3.2 g of the desired product as a yellow oil. 1e). (IS, 5R, 6R, 7R, ZP) -7-acetoxy-6- (E) -3-oxo-1-octane-6-ynyl-3- (4-methoxycarbonyl-1-buTN1) -2-oxa-6cyclo 3.3 .0 octane To a suspension of 96 mg of sodium hydride (50% suspension in oil) in 10 ml of dimethoxyethane, a solution of 53p mg of 2-oxo-hept-5-infosulfonic acid dimethyl ether in 2 ml of dimethoxyethane is added dropwise at room temperature and stirred for 2 hours at 23 ° C in argon. Then mixed at -20 ° C with a solution of 620 m of aldehyde prepared according to example 1d in 6 ml of dimethoxethane, stirred for 1.5 hours at -10 ° C, neutralized with acetic acid, diluted with ether, shaken with addition of 4% sodium bicarbonate solution and water, dried, magnesium sulfate and evaporated in vacuo. After purification by silica gel column chromatography, 654 mg of the expected product are obtained in the form of a white oil with ether / pentane (1: 1). , 2960, 1730, 1690, 1632, 1245,975. PRI me R
    [2]
    2. (IS, 5R, 6R, 7I, 3R) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (E) - (3S) -3-hydroxy-1-octane-6- ynyl -2-oxabicyclo 3.3.0 octane. 200 ml of the compound obtained in Example 1 are stirred for 16 hours at 25 ° C with a solution of 300 mg of sodium hydroxide in 10 ml of methanol and 1.6 ml of water. It is then concentrated in vacuo, diluted with 5 ml of brine, acidified with 10% citric acid solution to pH 5, extracted three times with methylene chloride, the extract is shaken with brine, dried with magnesium sulfate and evaporated in vacuo. After filtration with a small amount of silica gel, it is obtained by elution with chloroform containing 10% isopropanol, 140 mg of the desired product as an oil. IR, cm-: 3600, 3450, 2960, 1710, 978. Note
    [3]
    3. (IS, 5R, 68, 7R, 3S) -7-acetoxy-6 (B) - (3S) -3-rHflpoKCH-1-oKTeH-6-ynyl-3- (4-methoxycarbonyl-1-butyl) -2-oxabicyclo 3.3.0 octane. To a solution of 390 mg of (IS, 5R, 6R, 7R, 38) -7-acetoxy-6- (E) -3-oxo-1-octene-6-ynyl-3- (4-methoxycarbonyl-1-butyl) - 2-oxabicyclo 3.3.0 octane in 12 ml of methanol and 5 ml of tetrahydrofuran are added at -40 ° C in portions of 210 mg of sodium borohydride and stirred for 1 hour at -40 ° C. Then it is mixed with 0.5 ml of glacial acetic acid, concentrated in vacuo, the precipitate is mixed with methylene chloride, the organic extract is shaken with 4% sodium bicarbonate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with ether / pentane (6: 4), PO mg of the j3-configuration compound and 150 mg of the expected product are obtained in the form of an oil. The starting material for the compound described is prepared as follows. Behind). (IS, 5R, 6R, 7R, 3S) -7-acetoxy-6-benzyloxymethyl-3- (4-methy-carbonyl-1-butsh1) -2-, -oxabicyclo 3.3.0 octane. A solution of 300 mg of the 3S-configuration compound prepared in Example 16 (non-polar by-product), 0.3 ml of glacial acetic anhydride and 1 ml of pyridine were kept for 16 hours at room temperature and then evaporated in vacuo to give 0.32 g. product in the form of oil. IR, cm-: 2960.2940, 1732, 1245. 36). (18, 5R, 6R, 7R, 3S) -7-acetoxy-6-hydroxymethyl-3- (4-methoxycarbonyl-1-butyl) -2-oxabicyclo 3.3.0 octane. 0.8 g prepared according to the example. The compounds in 30 ml of ethyl acetate and 8 ml of ethanol are agitated with 150 mg of palladium (10% on coal) for 3 hours in hydrogen, filtered and evaporated in vacuo, to obtain 610 mg of the desired product as white oils. IR, cm-: 3600, 3450, 2960, 1732, 1245, Sv). (13, 5R, 6R, 7H, 3S) -7-acetoxy-6-formyl-3- (4-msoxycarbonyl-1-butyl) -2-oxabicyclo 3.3.0 octane. To a solution of 14 g of freshly obtained Collins reagent in 120 ml of abe. methylene chloride is added. at 0 ° C, a solution of 1.9 g of the compound obtained in example 36 in 50 ml of abs. methylene chloride. Stir for 30 minutes, mix with 35 ml of ether and shake four times with 20 ml of 4% sodium bicarbonate solution and twice with 30 ml of water. After drying over magnesium sulfate, it is evaporated in vacuo to give 1.5 g of the desired product as a gel. that oil. IR, cm-: 2960, 2870, 2720, 1730. Зг). (IS, 5R, 6R, 7R, 3S) -7-acetoxy-6- (E) -3-oxo-1-octene-6-ynyl-3- (4-methoxycarbonyl-1-butyl) -2-oxabicyclo 3.3 .0 octane To a solution of 190 mg of sodium hydride (50% suspension in oil) in 18 ml of dimethoxyethane, a solution of 1.06 g of 2-oxo-hept-5-in-phosphonate dimethyl ether in 4 ml of dimethoxyethane is added dropwise at room temperature and stirred 2 h at 22 ° C in argon. Then it is mixed at -20 ° C with a solution: 1.25 g of Zvaldehyde obtained in Example 10 in 10 ml of dimethoxyethane, stirred for 2 hours at -10 ° C, neutralized with acetic acid, diluted with ether, shaken with 4% sodium bicarbonate and water, dried with sulphate, magi, and evaporated in vacuo. After purification by chromatography on silica gel on a column, 1.35 g of the expected product is obtained in the form of an oil with ether / pentane (1: 1). IR, cm-: 2960, 1732, 1690, 1632, 1245, 975. Note
    [4]
    four.  (IS, 5R, 6R, 7R, 3S) -3- (4-carboxy-1-butyl) -7-hydroxy-b- (E) - (3S) 3-hydroxy-1-octene-6-unyl -1 -2 - oxabicyclo 3. 3 0 octane.  150 mg of the compound obtained in Example 3 were stirred for 16 hours at 25 ° C with a solution of 200 mg of sodium hydroxide in 7 ml of methanol and 1.2 ml of water.  It is then concentrated in vacuo, diluted with 5 ml of brine, acidified to pH 5 with 10% citric acid solution, extracted three times with methylene chloride, the extract is shaken once with brine, dried over magnesium sulfate and evaporated in vacuo.  After filtration with a small amount of silica gel, it is eluted with chloroform containing 10% isopropanol and 95 mg of the desired product as an oil.  IR, CM-J: 3640, 3440, 2960, 1710, 978.  Froze  (IS, 5R.  6R, 7R, 3R) -7-acetoxy-6- (E) - (ZS) -3-hydroxy-7-methyl-l, 6-octa-dienyl-3- (4-methoxycarboyl-1-butyl) -2 - oxabicyclo. 3 3 0 octane.  To a solution of 900 mg (18, 5R, 6R, 7R, 3R) -7-acetoxy-6- (1E) -7-methyl-3-oxo-1,6-octadienyl-3- (4-methoxycarbonyl-1-butyl ) - 2 - oxabidaclo 3. 3 0 octane in 28 ml of methanol and 11 ml of tetrahydrofuran is added in portions at -40 ° C with 460 mg of sodium borohydride and stirred for 1 hour at -40 ° C.  Then it is mixed with 1 ml of glacial acetic acid, concentrated in vacuo, mixed with methylene chloride, the organic extract is stirred up with 4% sodium bicarbonate solution, washed with water until neutral, dried over magnesium sulfate and evaporated in vacuo.  After chromatographic separation on silica gel, an ether / pentane mixture (1: 1) gives 270 mg of the corresponding compound / 3-configuration and 293 mg of the expected product in the form of an oil.  The starting material for the described compound is obtained in the following manner.  5a).  (18, 5R, 6R, 7R, 3R) -7-acetoxy-6- (1E-7-methyl-3-oxo-1,6-octadienyl-3- (4-methoxycarbonyl-1-butyl) -2-oxabitslo 3 3 0 octane 3.1 g of aldepvda prepared according to example 1d and 4.2 g (6-methyl-2-oxo-5; heptenylidene) -triphenylphosphorane are dissolved in 80 ml of abs.  Bin5 8 ash and stirred for 7 h at room temperature in argon.  The solution is then concentrated on a rotary dryer to dryness and the precipitate is purified by chromatography on a silica gel on a column and with ether / pentane (1: 1) to give 2.9 g of the title compound as an oil.  IR, cm-: 2960, 1732, 1690, 1630, 1245.976.  PRI me R 6.  (18, 5R, 6R, 7R, 3R) -3- (4-carboxy-1-butyl) -7-padroxy-6- (IE) - (38) -3-hydroxy-7-methyl-1,6- octa-dienyl -2-oxabicyclo 3. 3 0) octane.  220 mg of the compound obtained in Example 5 were stirred for 16 hours at 25 ° C with a solution of 300 mg of sodium hydroxide in 10 ml of methanol and 1.6 ml of water.  It is then concentrated in vacuo, diluted with 5 ml of brine, acidified to pH 5 with 10% citric acid solution, extracted three times with methylene chloride, the extract is shaken with brine, dried over magnesium sulfate and evaporated in vacuo.  After filtration through silica gel, chloroform containing 10% isopropanol is obtained, 150 mg of the title compound as an oil.  IR, cm-: 3620, 3450, 2960, 1712, 978.  PRI me R 7.  (18, 5R, 6R, 7R, 38) -7-acetoxy-b- (IE) - (38) -3-hydroxy-7-methyl-1,6-ca a-dienyl-3- (4-methoxycarbonyl- 1-butyl) 2-oxabicyclo 3. 3 0 octane.  To a solution of 470 mg (IS, 5R, 6R, 7R, 3S) -7-acetoxy-6- (E) -7-methyl-3-oxo-1,6-octadienyl-3- (4-methoxycarbonyl-1-butkl ) -2-oxabicyclo 3.3. 0 oioaH and 14 ml of methanol and 4 ml of tetrahydrofurap are added at -40 ° C in portions of 230 mg of bo | sodium hydride and stirred for 1 hour at -40 ° C.  Zahem is mixed with 0.6 ml of glacial acetic acid, concentrated in vacuo; they are mixed with methylene chloride, the organic extract is stirred with 4% sodium bicarbonate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo.  After chromatographic separation on silica gel, 1: 1 with ether / pentane (120) is used. 120 mg of the corresponding compound / 3-configuration and 160 mg of the expected product are in the form of a white oil.  IR, 3640, 3460, 2960, 1730, 978.  The starting material for the described compound is prepared as follows.  7a) (IS, 5R, 6R, 7R, 38) -7-acetoxy-6 - (} E) -7-methyl-3-oxo-, 6-octa-diennl-3- (4-methoxycarbonsh-β-butyl) -2-oxabicyclo 3. 3 0 octane.  Analogously to example 5a, from 1.58 g obtained according to the example of Zv aldehyde and 2.1 g (6-methyl-2-oxo-5-heptensteride) -triphenylphosphorane, 1.4 g of the title compound are given in the form of an oil.  Approx 8.  (IS, 5R, 6R, 7R, 3S) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (lE) - (3S) -3gdroxy-7-methyl-1,6-octa dienyl 2-oxabicyclo 3. 3 0 octane.  Analogously to example 6, out of 140 mg of the compound obtained in example 7, 83 mg of the desired compound are obtained in the form of an oil.  IR, cm-: 3620, 3450, 2960, 1712, 978.  PRI me R 9.  (IS, 5R, 6R, 7R, 3R) -7-acetoxy-6-l (E) - (3RS) -3-rHApoKCH-3-MeTmi-l-octene-6-ynyl - 3- (4-methoxycarbonyl- 1-butyl) -2-oxabicyclo 3. 3 0 octane.  To a solution of 3 g of the ketone prepared in Example 1e in 120 ml of abs.  tetrahydrofuran is added dropwise at -60 ° C with 10 ml of ethereal methyl 1 solution; Neibromide (prepared from 0.05 g-atom of magnesium), stirred for 30 minutes, poured with 100 ml of saturated ammonium chloride solution, stirred at 20 ° C 10 times, four times extracted with 150 ml of ether each time, the organic extract is washed with water until.  neutral, dried with magnesium sulfate and evaporated in vacuo.  After purification on a column by silica gel chromatography, 2.6 g of the title compound is obtained as ether / pentane (8: 2) as an oil.  IR, cm-: 3600, 3450, 2960, 1732, 975.  I'll try it on.  (18, 5R, 6R, 7R,) -3- (4-ka rboxy-1-butyl) -7-hydroxy-6- (E) - (3RS) -3-hydroxy-3-methyl-1-octane- 6; Silt-2-oxabicyclo 3: 3. 0 octane.  Analogously to Example 2, from 410 mg of the compound obtained according to Example 9, 305 mg of the title compound are obtained as a white oil.  IR, cm-: 3600, 3450, 2960, 1710, 978.  Example I.  (13, 5R, 6R, 7R, 3S) -7-acetoxy-6- (E) - (SNP) -3-hydroxy-3-methyl-1-octene-6-ynyl-3- (4-methoxycarbonyl-1 -butyl-2goxabicyclo 3. 3 0 octane.  Analogously to Example 9, from 0.9 g of the obtained by Example 3g of ketone, 0.68 g of the title compound is obtained as an oil. .  IR, 3600, 3450, 2960, 1710, 978.  PRI me R 12.  (IS, 5R, 6R, 7R, 3S) -3- (4-carboxy-1-butyl) -7-gvdroxy-6- (B) - (3RS.  -3-hydroxy-3-methyl-1-octene-6-ynyl-2-oxabicyclo 3. 3 0 octane.  In a similar manner to Example 2, out of 380 mg, obtained: In the example of Example P of the compound, 288 mg of the title compound was obtained as an oil.  PRI me R 13.  (IS, 5R, 6R, 7R, 3R) -7-acetoxy-6- (IE) - (ЗRS) -3,7-dimethyl-3-hSi-1.6-octa-dienyl-3- (4- methoxycarbonyl-1-butyl) -2-oxabicyclo 3. 3 0 octane.  Analogously to Example 9, 0.6 g of the title compound in the form of an oil is obtained from 0.8 g of the ketone obtained in Example 5a.  PRI me R 14.  (IS, 5R, 6R, 7R, 3R) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (1E) (3RS) -3,7-dimethyl-3-hydroxy-1,6 octadienyl 2-oxabicyclo 3. 3 0 octane.  Analogously to Example 2, out of 320 mg of the compound obtained in Example 13, 245 mg of the intended compound are obtained in the form of an oil.  IR, 3600, 3340, 2965, 1710, 978.  .  PRI me R 15.  (IS, 5R, 6R.  7R, 3S) -7-acetoxy-6- (IE) - (ZRS) -3,7-dimethyl-3-hydroxy-1, 6-octa-dienyl-3- (4-methoxycarbonyl-1-, -butyl) -2-oxabicyclo 3. 3 0 octane.  Analogously to Example 9, from 0.6 g of the ketone prepared in Example 7a, 0.46 g of the target compound are obtained in the form of an oil.  Example 16  (18, 5R, 6R, 7R, 33) -3- (4-carboxI1-butnl) -7-hydroxy-6- (1E) - (3RS) -3,7-dimethyl-3-hydroxy-1,6- Octa-NideNide} -2-oxabicyclo 3. 3 0 octane.  Analogously to example 2 of 0.4 g obtained; According to Example 15 compounds, 0.3 g of the title compound is obtained as an oil.  IR, cm-: 3620, 2965, 1710, 978.  Example 17  (IS, 5R, 6R, 7R, 3R) -7-acetoxy-6- (E) - (3S, 4RS) -3-hydroxy-4-mutewI-1 - octene 6-butyl-ynyl - 3- (4 - methoxycarbonyl-1-butyl) -2-oxabicyclo 3. 3 0 octane.  To a solution of 440 mg of the ketone prepared in Example 17a in 14 ml of methanol and 5 mp THF, 220 mg of sodium borohydride was added at -40 ° C, and stirred at -40 ° C for 45 minutes.  Then it is carefully mixed with 1-1 ml of glacial acetic acid, concentrated in vacuo, the precipitate is mixed with methylene chloride, and the organic extract is shaken with 4% sodium bicarbonate solution, etc.  wash with water until neutral and incubate in vacuo.  After chromatography of the residue on a C1 gel, with ether / pentane (6: 4), 140 mg of the | 3-configuration compound and 155 mg of the desired compound are obtained in the form of a white oil.  IR (СНС1з), cm-: 3600, 3950, 2960, 1732, 976. The starting material for the described compound is prepared as follows.  17a).  (IS, 5R, 6R, 7R, 3R) -7-acetoxy-6- () - (4RS) -4-methyl-3-ox-1-octene-6-ynyl-3- (4-methoxycarbonyl-1- butyl) -2-oxabicyclo 3. 3 0 octane.  To a suspension of 192 mg of sodium hydride (50% in oil) in 20 ml.  dimethoxyethane is added dropwise at. Noah temperature solution. 1.05 g of 3-metsh-2-oxo-hept-5-in-phosphonate dimethyl ether in 4 ml of dimethoxyethane and stirred for 2 hours at 23 ° C in argon.  Then, at -20 ° C, a solution of g of the aldehyde prepared in Example 1d in 12 ml of dimethoxyethane is mixed, stirred at -10 ° C for 1.5 h, neutralized with acetic acid, diluted with ether, shaken with 4% sodium bicarbonate solution and water dried with magic sulphate and evaporated in vacuo.  After purification by column chromatography on silica gel, with ether / pentane (1: 1), 1.31 g of the title compound are not obtained in the form of an oil.  IR, 2960, 1730, 1690, 1630, 1245, 976.  PRI me R 18.  (IS, 5R, 6R, 7J, 3R) -3- (4-carboxy-b-butyl) 7-hydroxy-6- (E) - (3S, 4P8) -3-hydrox-4-methyl-1-octane-6 -Insh1 -2-oxabisl 3. 3 0 octane.  The analogs "in Example 2 of 140 mg of the compound obtained in Example 17 receive 85 mg of the target compound in the form of poor IR oil, cm-H 3600, 3450, 2960, 1712, 978.  , Example 19. (IS, 5R, 6R, 7R, 3S) -7-acetoxy-6- (E) - (3S, 4RS) -3-hydroxy-4-methyl 1-octene-6-ynyl-3- (4-methoxycarbonyl- l -butyl -2-Ocboxits 3. 3 0 octane. .  To a solution of 800 mg of the ketone obtained in Example 19a in 24 ml of methanol and 10 ml of tetrahydrofuran are added at -40 ° C partly 420 mg of sodium borohydride and stirred for 1 hour at -40 ° C.  Then, gently mix C with 1 ml of glacial acetic acid, concentrate in vacuo, mix the precipitate with methylene chloride, shake the organic extract with 4% solution. sodium bicarbonate, washed with water until neutralization of the reaction and evaporated in vacuo.  After chromatography of the residue, 230 mg of alcohol are obtained with ether / pentane (1: 1); c / 3 configuration and 260 m of the title compound as a white oil.  IR, cm-: 3650, 3450, 2960, 1730, 978.  19a).  (IS, 5R, 6R, 7R, 3S) -7-aneTOKCH-6- (Е) - (4Я5) -4. -methyl-3-oxo-1-octene-6-yn.  -3- (4-methoxycarbonyl-1-butyl) -2-oxabicyclo (3. 3 01 octane.  Analogously to Example 17a, from 0.55 g of 3-methyl-2 oxo-hept-5-in-phosphonate dimethyl ether and 0.6 g of the aldehyde obtained in Example H, 0.68 g of the title compound is obtained as an oil.  Example 20  (IS, 5R, 6R, 7R, 3S) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (E) - (3S, 4RS) -3-hydroxy-4-methyl 1-octene -6-ynyl -2-oksab1ShKklo 3. 3 0 octane.  Analogously to Example 2, out of 180 g of the compound obtained in Example 19, 110 mg of the desired compound is obtained in the form of a white oil IR, 3600, 3430, 2960, 1712, 976.  Example 21  (IS, 5R, 6R, 7R, 3R (-7-acetoxy-6 (IE) - (3S, 4RS) -4,7-dimethyl-3-hydr.  hydroxy-1,6-octadienes -3- (4-methoxycarboIl-l-byTI) 2-octabicyclo 3. 3 0 octane.  To a solution of 440 mg of the ketone prepared in Example 21a in 14 ml of methanol and 5 ml of tetrahydrofuran are added in portions at -40 ° C with 230 mg of sodium borohydride and stirred at -40 ° C for 1 hour.  Then it is carefully mixed with 0.6 ml of glacial acetic acid, concentrated in vacuo, mixed with methylene chloride, the organic extract is shaken with 4% sodium bicarbonate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo.  After chromatographic separation on silica gel, with ether / pentane (1: 1), 140 mg of the 0-configuration compound and 145 mg of the desired compound are obtained in the form of an oil.  IR, 3600, 3450, 2960, 1732, 978.  The starting material for the described compound is prepared as follows.  21a).  (IS, 5R, 6R, 7R, 3R) -7-aHeTOKcn-6- {(IE) - (4RS) -4,7-dimets-3-oxy-6, 6-octane 3- (4-methoxy-carbonyl - 1-butyl) - 2-oxabicyclo 3. 3 0 octane.  To a suspension of 100 mg of sodium hydride (50% suspension in oil) in 8 ml of dimethoxyethane is added dropwise at 23 ° C. S50 mg of 2-oxo-3,6-dimethyl-hept-5-enophosphono-dimethyl: zfir in 3 ml of dimethoxyethane and stirred at 23 ° C for 2 hours in argon.  Then mixed at -20 ° C with a solution of 620 mg of floor) D1enn of Example 1d aldehyde in 6 ml of dimethoxyethane, stirred for 1.5 hours at -10 ° C, neutralized with acetic acid, diluted with ethers; shaken with 4% solution sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo.  After purification by silica gel column chromatography, 590 mg of the title compound are obtained as ether / pentane (4: 6) as an oil.  IR, cm: 2960, 1730, 1690, 1630, 1245, 976.  The phosphonate required for Example 21a was prepared as follows.  216).  (2-oxo-3,6-dimethyl-hept-5-en-phosphonate dimethylether.  To suspension 4.5 g of sodium hydride (50%. -on suspension in oil) in 160 ml of abs.  tetrahydrofuran is added dropwise at 24 ° C to a solution of 17 g of 2-oxo-butyl-phosphonoxyl dimethyl ether in 160 ml of tetrahydrofuran, stirred for 1.5 h and then 83 ml of a 1.24 molar solution is added dropwise at 24 ° C butyl lithium in hexane and mix for 20 minutes.  Then a solution of 15.5 g of 4-bromo-2-methyl-2-butene in 40 ml of abs is added dropwise to this mixture at 0 ° C.  tetrahydrofuran, stirred for 1 h, neutralized with 3 g of hydrochloric acid and concentrated in vacuo.  It is mixed with 50 ml of brine, extracted three times with 100 ml of methylene chloride, twice heated with 50 ml of brine, dried over magnesium sulfate and evaporated in vacuo.  After distillation of the precipitate through a tube with a spherical expander at 13: 150 ° C / 0.5 mm, 13.5 g of the desired compound are obtained in the form of a colorless liquid.  IR, 3600, 2960, 2915, 2863, 1720, 1260, 1040.  PRI me R 22.  (IS, 5R, 6R, 7R, 3R) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (1E) - (3S 4RS) -4,7-dimethyl-3-hydroxy-1 , 6-octadanyl -2-oxabicyclo 3. 3 0 rktan  Analogously to Example 2, out of 210 mg of the compound obtained in Example 21, 160 mg of the title compound are obtained as a mass.  IR, cm-: 3640, 3450, 2960, 1710, 978.  , PRI me R 23.  (IS, 5R, 6R, 7B, 3S) -7-acetoxy-6- (IE) - (3S, 4RS) -4,7-dimethyl-3-hydroxy-1,6-octadienyl-3- (4-methoxycarbonyl -1-butyl) -2-oxabicyclo 3. 3 0 oirtaH.  To a solution of 780 mg of the ketone prepared in Example 23a in 24 ml of methanol and 8 ml of tetrahydrofuran were added at -40 ° C in parts of 420 mg of sodium borohydride and shifted at -40 ° C for 1 hour.  Then it is mixed with 1 ml of glacial acetic acid, concentrated in vacuo, the precipitate is mixed with methylene chloride, the organic extract is shaken with 4% sodium bicarbonate solution. It is washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo.  After chromatography of the residue on silica gel, 260 mg of the alcohol c) the 3-configuration and 255 mg of the target compound are obtained in oil form with ether / pentane (1: 1).  IR, 3600.2960, 1732, 1245, 976.  The starting material for the described compound is prepared as follows. in a way.  23a).  (IS, 5R, 6R, 7R, 38) -7-acetoxy-6- (IE) - (4RS) -5,7-dimethyl-3-oxo-1,6-octadienyl - 3- (3-methoxycarbonyl) 1-butyl) - 2-oxabicycl 3. 3 0 octane.  Analogously to Example 21, from 1.2 g of 2-oxo-3-dimethyl-hept-5-ene-phosphonate dimethyl ether and 1.25 g of the aldehyde prepared according to Example H, 1.28 g of the title compound are obtained as an oil.  PRI me R 24.  (IS, 5R, 6R, 7R, 3S) -3 (4-carboxy-1-butyl) -7-hydroxy-6-1E) - (3S, 4RS) -4,7-dimethyl-3-hydroxy-1, 6-octadienyl -2-oxabicyclo 3. 3 0 octane.  Analogously to Example 2, out of 290 mg of the compound obtained in Example 23, 190 mg of the target soy are obtained, as an oil.  Example 25  (IS, 5R, 6R, 7R, 3R) -7-acetoxy-6- (E) - (3R) -4,4-dimethyl-3-hydroxy-1-octene-6-ynyl-3- (4-methoxy -carbonyl- 1-butyl) -2-oxabicyclo 3. 3 0 octane.  To a solution of 410 mg of the ketone obtained in Example 25a in 14 ml of methanol and 5 ml of tetrahydrofuran are added, at -40 ° C, 220 mg of sodium hydride and stirred at 40 ° C for 1 h. , mix the sediment with methylene chloride, stir the organic extract with 4% sodium bicarbonate solution, wash with water until neutral, and evaporate in vacuo.  After x: chromatography of the residue on silica gel, 123 mg / 3-alcohol and 140 mg of the expected compound are obtained as ether / pentane (6: 4) as an oil.  IR, cm-: 3640, 3450, 2965, 1732, 978.  The starting material for the described compound is prepared as follows.  25a).  (IS, 5R, 6R, 7R, 3V) -7 acetoxy-6 (E) -4,4-dimethyl-3-oxo-1-octene-6-ynyl-3- (4-methoxycarbonyl-1-butyl) - 2-oxabicyclo 3. 3 0 octane.  To a suspension of 192 mg of sodium hydride (50% suspension in oil) in 20 ml of abs.  dimethoxyethane is added dropwise at 23 ° C to a solution of 1.1 g of 3,3-dimethyl-2-oxo-hept-5-infophosphonate dimethyl ether in 4 ml of dimethoxyethane and stirred at 23 ° C for 2 hours in argon.  Then, 1.24 g of the aldehyde prepared in Example 1d in 12 ml of dimethoxyethane is mixed with a solution, stirred at -10 ° C for 1.5 hours, neutralized with acetic acid, diluted with ether, and stirred with a 4% solution. sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo.  After purification by chromatography on silica gel on a column, get with e. phyr / pentane (1: 1) 1.28 g of the title compound as a white oil.  PRI me R 26.  (18, 5R, 6R, 7R, 3W) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (E) - (3R) -4, 4-dimethyl-3-hydroxy-1 - Octen-6-innl -2-oxabicyclo 3. 3 0 octane.  Analogously to Example 2, from 180 mg of the compound obtained in Example 25, 120 mg of the title compound are obtained as an oil.  IR, cm-: 3600, 3450, 2960, 1710, 976.  PRI me R 27.  To a solution of 380 mg of the ketone obtained in Example 27a in 13 ml of methanol and 4 ml of tetrahydrofuran are added at -40 ° C 210 mg of sodium bordegium and stirred for 1 hour at -40 ° C.  Mix with 1 ml of glacial acetic acid, concentrate in vacuo, mix the precipitate with methylene chloride, shake the organic extract with 4% sodium bicarbonate solution, wash with water until neutral, and evaporate in vacuo.  After chromatographic separation of the residue on silica gel, 143 mg of the expected compound are obtained in the form of an oil with ether / pentane (6: 4).  The starting material for the described compound is prepared as follows.  27a).  (IS, 5R, 6R, 7R, 35) -7-acetoxy-6- (E) -4,4-dimethyl-3-oxo-1-octene-6-ynyl-3- (4-methoxycarbonyl-1-butyl ) -2-oxabicyclo 3. 3 0 octane.  Analogously to example 25a, from 0.6 g of 3,3-dimethyl-2-oxo-hept-5-phosphonate dimethyl ether and 0.55 g obtained according to the example of Exterior Aldegvd get 0.59 g of the desired compound as an oil.  PRI me R 28.  (IS, 5R, 6R, 7R, 3S) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (E) - (3R -4,4-dimethyl-3-hydroxy-1-octene -6-ynyl -2-oxabicyclo 3. 3 0 octane.  Analogously to example 2 of 160 mg semi.  In a compound of Example 27, 105 mg of the title compound was obtained as an oil.  JK, 3610, 3450, 2965, 1710, 978.  PRI me R 29.  (IS, 5R, 6R, 7R, 3R) -7-acetone-b-IE) - (3R) -3-hydroxy-4,4,7-trimethyl-1,6-octadien-1 -3- (4-methoxycarbonyl) butyl) -2-oxabicyclo 3. 3 0 octane.  To a solution of 400 mg of the ketone prepared in Example 29a in 14 ml of methanol and 4 ml of tetrahydrofuran are added with 230 mg of sodium hydride bo and stirred at -40 ° C for 1 hour.  Mixed with 1 ml of glacial acetic acid, concentrated in vacuo, mixed with methylene chloride, shaken with 4% sodium bicarbonate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo.  After chromatographic separation on silica gel with ether / pentane (6: 4), 154 mg of the title compound are obtained as a white oil.  The starting material for the described compound is prepared as follows.  29a).  (IS, 5R, 6R, 7R, 3R) -7-aneTOKCH-6-1E) -3-oxo-4,4,7-trimethyl-1,6-octadienyl-3- (4-methoxycarbonyl-1-butyl) -2-oxabicyc 3. 3 0 octane.  1.6 g of aldehyde prepared according to Example 1d and 2.3 g of (3,3,6-trimethyl-2-oxo-5-heptenshidene) -triphenylphosphorane in 40 ml of abs.  benzene is stirred for 16 hours at room temperature in argon.  The solution is then evaporated, and the residue is purified by chromatography on silica gel on a column of ether / pentane (1: 1), to give 0.8 g of the title compound as an oil.  PRI me R 30.  (IS, 5R, 6R, 7R, 3R) -3- (4-carboxy-1-butyl) -7-hydroxy-6- () - (3 R) - 3-hydroxy-4,4,7-trimethyl- 1,6-octadienes -2-oxabicyclo 3. 3 0 octane.  Analogously to Example 2 of 130 mg of the compound obtained in Example 29, 82 mg of the desired compound are obtained in the form of an oil.  IR   3600, 3400, 2965, 1710, 978; 5J6, Example 8, p 31.  (IS, 5R, 6R, 7R, 3S) -7.  -acetoxy-6- (1E) - (3R) -3-hydroxy-4,4,7-trimethyl-1, 6-octadienyl-3- (4-methoxycarbonyl-1-butyl) -2-Rxabicyclo 3. 3 0 octane.   To a solution of 395 mg of the ketone prepared in Example 31a in 14 ml of methanol and 4 ml of tetrahydrofuran, 230 mg of sodium borohydride are added at -40 ° C and stirred at -40 ° C. I h.  Mixed with 1 ml of glacial acetic acid, concentrated in vacuo, mixed with methylene chloride, shaken with 4% sodium bicarbonate solution, washed with water until neutral, dried with MajTHHH sulfate and evaporated in vacuo.  After chromatographic separation on silica gel, a yield is obtained. with ether / pentane (6: 4) 133 mg of the title compound as an oil.  The starting material for the described compound is prepared as follows.  31a).  (18, 5R, 6R, 7R, 38) -7-acetoxy-6- (lE) -3-oco-4, 4,7-trimethyl-1,6-octadienyl (4-methoxycarbonyl-1-butyl) -2 - oxabile 3. 3 0 octane.  Analogously to example 25a, 0.62 g of the title compound is obtained in the form of an oil from 1.4 g of a crawl of the example of the addition of aldehyde.  PRI me R 32.  (IS, 5R, 6R, 7R, 3S) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (IE) - (3R) -3-hydroxy-4, 4,7-trimethyl- 1,6-octadienyl -2-oxabicyclo 3.  octane.  Analogously to Example 2, out of 140 mg of the compound obtained in Example 31, 90 mg of the title compound are obtained as an oil.  IR,, 3400, 2965, 1710; 978.  PRI me R 33.  (IS, 5R, 6R, 7R, 3R) -6- (E) - (35) -3-hydroxy-1-octene-6-ynyl-7-hydroxy-3- (4-methylsulfonylcarbamoyl-1-butyl) - 2-oxabicyclo 3. 3 0 octane.  400 mg (IS, 5R, 6R, 7R, 3R) -3- (4-cara, boxy-1-butyl) -7-hydroxy-6- (E) - (3S) -3-hydroxy-l-octene b-ynyl -2-oxabicyclo 3. 3 0 octane (see  Example 2) dissolved in 1 ml of pyridine and 0.5 ml of acetic anhydride and 100 mg of 4-dimethylaminopyridine are incubated overnight at room temperature, then mixed with 0.2 ml of water, again settled for 2 hours, diluted with 50 ml of water and extracted several times with methylene chloride, shaken the extract alternately with dilute sulfuric acid and brine, dried with magnesium sulfate and evaporated in vacuo.  The obtained diacetate is dried in vacuum at 40 ° C / 0.01 mm for 1 h, then dissolved in 25 ml of dry tetrahydrofuran and mixed with 1.5 ml of triztilamine.  160 mg of methanesulfonyl isocyanate dissolved in 10 ml of tetrahydro-furan are added dropwise to this solution and stirred at 20 ° C for 6 hours.  17 After neutralization with acetic acid, evaporated in vacuo, the precipitate is dissolved in 50 ml of chloride chloride. The mixture is stirred with a saturated solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo.  To remove the protective group, the precipitate was stirred at 20 ° C for 16 hours with a solution of 400 mg of sodium hydroxide in 12 ml of methanol and 2 ml of water.  It is then concentrated in vacuo, diluted with 15 ml of brine, acidified to pH 5 with 10% citric acid solution, extracted several times with methylene chloride, the extract is shaken with brine, dried over magnesium sulfate and evaporated in vacuo.  After chromatography of the precipitate on 10 g of silica gel with chloroform containing 10% isopropanol, 185 mg of the expected compound are obtained in the form of an oil.  IR, 3600, 3380, 2945, 1720, 976.  Example 34  {IS, 5R, 6R, 7R, 3S) -6- ((E) - (35) -3-hydroxy-1-octene-b-ynyl-7-hydroxy-3- (4-methylsulfonone1carbamoyl-1-butyl) -2-oxabicyclo 3. 3 0 octane.  According to Example 33, out of 340 mg (IS, 5R, 6Н, 7R, 3S) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (Е) - (ЗВ) -3-hydroxy-1- octene-6-ynyl -2-oxabicyclo 3. 3 0 octane gives 90 mg of the title compound.  IR, 3600, 3385, 2945, 1718, 976.  PRI me R 35.  (IS, 5R, 6R, 7R, 3R) -6- (E) - (38) -3-hydroxy-7-methyl-1,6-octadien-b -yl-7-hydroxy-3- (4-methylsulfonylcarbamoyl -1-butsh1) -2-oxabicyclo 3. 3 0 octane.  According to Example 33, out of 400 mg (IS, 5R, 6R, 7R, ЗR) -3- (4-box-1-butyl) -7-hydroxy-6- (E) - (ZS) -3-hydroxy-7-methyl l, 6-octadienyl -2-oxabicyclic 3. 3 0 octane (see  Example 6) 210 mg of the title compound as an oil is obtained.  IR, cm-: 3600, 3390, 2955, 1718, 978.  PRI me R 36.  (IS, 5R, 6R, 7R, 3S) -6- (E) - (3S) -3-hydroxy-7-methyl-l, 6-octadien-l-yl-7-. hydroxy-3- (4-methylsulfonylcarbamos-1-butyl) -2-oxabicyclo 3. 3 0 octane.  According to example 33 of 300 mg.  (IS, 5R, 6R, 7R, 38) -3- (4-carboxy-1-butyl) -7-hydroxy: -6- (IE) - (38) -3-hydroxy-7-methyl-1.6 octadiene.  ; Yu1 -2-oxabicyclo 3. 3 0 octane (see  Example 8) obtain 155 mg of a chain-based compound as an oil.  IR, cm-: 3610, 3485, 2955, 1720, 978.  PRI me R 37.  (IS, 5R, 6R, 7R, 3R) -6- (E) - (3P) -4,4-dimethyl-3-hydroxy-1-octene-6-ynyl-7-hydroxy-3- (4-methylsulfonylcarbamO il-1-butyl) -2-oxabiylclo 3. 3 0 octane.  According to Example 33, out of 300 mg (IS, 5R, 6R, 7R, 3R) -3- (4-carboxy-1-butyl) -7-hydroxy-6- (6) - (ЗR) -4,4-dimethyl- 3-gkdroksi-I-Okten-65-insh1-2-oxabicyclo 3. 3 0 octaia (see  Example 26) 180 mg of the title compound are obtained as an oil.  IR, 3600, 3480, 2955, -1718, 976.  PRI me R 38.  (IS, 5R, 6R, 7R, 3R) -6- (E) - (38) -3-yr) oxy-1-octene-6-ynyl-7-hydroxy-3- (4-isopropylsulfonylcaro-amoyl-1-butkl ) -2-oxabicyclo 3. 3 0 octane.  A solution of 500 mg (IS, 5R, 6R, 7R, 3R) -3- (4-carboxy-1-butyl) -7-pzdroxy-6-l (E) - (3S) -3-hydroxy-1-octene 6-ins1 -2-oxabicyclo.  3 3 0 octane (see  Example 2), 100 mg of 4-imethylaminotshoridine and 0.5 acetic anhydride in 1 ml of pyridine are kept at room temperature for 4 hours, mixed with 0.2 ml of water, stirred for 2 hours, diluted with 50 ml of brine and extracted several times with methylene chloride .  The extract is shaken with dilute sulfuric acid and brine, dried over magnesium sulfate and evaporated in vacuo.  The dried precipitate (for 1 hour at 40 ° C / 0.01 mm) is dissolved in 25 ml of dry tetrahydrofuran and the solution is alternately mixed with 1.5 ml of triethylamine and a solution of 250 mg of isopropylsulfonyl isocyanate in 15 ml of tetrahydrofuran, and the mixture is stirred for 6 hours at 20 ° C. neutralize with acetic acid and evaporate the solvent in vacuo.  The precipitate is dissolved in 100 ml of methylene chloride, the solution is agitated with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo.  To remove the protective acetate groups, the precipitate was stirred for 16 hours at. 20 ° C With a solution of 450 mg of sodium hydroxide in 14 ml of methanol and 2 ml of water.  It is then concentrated in vacuo, diluted with 20 ml of brine, acidified to pH 5 with 10% citric acid solution, extracted several times with methylene chloride, the extract is shaken with brine, dried over magnesium sulfate and evaporated in vacuo.  After chromatography on 10 g of silica gel, chloroform containing 10% isopropanol is obtained, 280 mg of the title compound as an oil.  IR, 3600, 3385, 2960, 1720, 976.  Example 39  (IS, 5R, 6R, 7R, 3R) -6-1 (B) - (38) -3-hydroxy-7-methyl-1,6-octadienyl-1-yl-7-hydroxy-3- (4- isopropylsulfonylcarbamoyl -} - butyl) -2. -oxabic 3. 3 0 octane.  According to example 38 of.  300 mg (IS, 5R, 6R, 7R, ЗR) -3- (4-box-1-butyl) -2-gi-roxy-6- (IE) - (3S) -3-hydroxy-7-methyl-1 , 6-octa-dienyl -2-oxabicyclo 3. 3 0 octane (see  Example 6) obtain 145 mg of the title compound as an oil.  IR, cm-: 3600, 3485, 1715, 978.  PRI me R 4a (IS.  5R, 6R, 7R, 3R -6-t (E) - (Z5) -3-p fv "; w-3-etn - Gokte-b-ynil-7-hydroxy-3- (4-nzaroz euYa fsiylka | 5bamo1Sh -1-butyl) -2-vk “th tnklo 13. 3 0} ekta.  According to Example 33 of 300 mg (IS, 5R, 6R, 7R, 3R) -3- (4-Kap6oK ai-l-6yTHn) -7-rHapoKOT -6- (Е) - (ЗВ8) -3-пвдроккс11-3 -methyl-1-octa-6-vin-2-oxabicyclo (Z. H. a) Octm obtained 180 mg of the title compound as mael.  IR, 3610, 3485, 1718, 978.  PRI me R 41.  (13, 5Я, 6R, 7R, 3R) -6- (E) - (3S, 4flS) -3-gvdrokomM-metn-1-octene-6-ynyl} 7-g1 drottss -3-4- | zooMy sulfonylcar6amo t-1-butyl) -2-ok ha6 pdaslo (3. 3.01 octane.  ,  According to example 58, out of 400 mg (18, 5R, 6B, 7R, ЗR) -3- (4-chr. Bytlm) -7-hydrox-6-E3) - (3S, 4YZ) -3-hl and xi-4- methyl 1-octene-6-inip -2-0xabicyclo 3. 3 0 octa (see  Example 18) 230 mg of the title compound are obtained as an oil.  IR, 3600, 3485, 2950, 1715, 976.  PRI me R 42.  (IS, 5R, 6R, 7R, 3R) -6-f (E) - (3S, 4RS) -4.7 dimethyl-3-r and ox-1, 6-octadien-1-yl-7-hydroxy-3 - (4-isopropylsulfonylcarbamoyl-1-butyl) -2-oxabicyclo <3. 3 0 octane.  Analogously to example 38, 95 mg of the carboxylic acid obtained according to example 22 receive 95 mg of the target compound in the formulations of IR, 3600, 3480, 2955, 1718, 976.  PRI me R 43.  (IS, 5R, 6R, 7R, 3R) -6- {(E) - (3R) -4,4-dimethyl-3-subproxix 1-octe-6-ynyl-7-P1Droxy-3- (4- isoproshsulfonylcarbamoyl-1-butyl) -2-oxabicyclo (3. 3 0 okta Analogously to example 38, of 400 mg of the carboxylic acid obtained in example 26, 225 mg of the desired compound are obtained in the form of an oil.  IR, 3600, 3480, 2950, 1715, 976.  PRI me R 44.  (18, 5R, 6R, 7R,: iR) -6- ((E) (ЗR) 3-p dicro-4,4,7-trimethyl, 6-octadien-1-yl-7-hydroxy-3- ( 4-Isopropylsulfur carbamoyl-1-butyl) -2-oxabicyclo 3. 3 0 octane.  Analogously to example 38, from 400 mg of the carboxylic acid obtained in example 30, 205 mg of the desired compound are obtained in the form of an oil.  IR  3600, 3480, 2950, 1718, 978.  According to Example 39, using the carboxylic acids prepared according to Examples 4, 8, 12, 14, 16, 20, 24, 28 and 32, the corresponding isopropylsulfonylcarbamoyl compounds are prepared.  PRI me R 45.  (IS, 5R, 6R, 7R, 3R) -3- (4-acetylcarbamoyl-1-butyl-6- (E) - (3 S) -3-hydroxy-1-octene-6-inyl-7-hydroxy- 2-oxabicyclo 3. 3 0} octane.  400 mg (IS, 5R, 6R, 7R, 3R) r3- (4-Kap6oKCH-1-butyl) -7-hydroxy-6- (E) - (3 8) -3 - hydra xi-1-octene-6 vinyl -2-oxabicyclo 3. 3 0 octane, 100 mg of 4-dimethylaminopyridine, 0.5 ml of acetic anhydride and 1 ml of pyridine are stirred at 20 ° C for 16 hours, mixed with 0.2 ml of water, mixed again for 2 hours, diluted with 50 ml of water and extracted several times with chloride with methylene, agitate the extract alternately with dilute sulfuric acid and brine, dry with magnesium sulfate, and extract in vacuum.  The dried precipitate (for 1 hour at 40 ° C and 0.01 mm) is dissolved in 15 ml of acetonitrile and then a solution of 150 mg of acetyl isocyanate in 10 ml of acetonitrile is added dropwise to it at 0 ° C.  Stir again for 2 hours at 20 ° C, concentrate in vacuo, acidify to pH 5 with dilute sulfuric acid, extract several times with ether and wash the extract with brine until neutral, dry with magnesium sulfate and evaporate in vacuo. .  To precipitate protective acetate groups, the precipitate is stirred for 5 hours at 20 ° C with a solution of 200 mg of sodium hydroxide in 10 ml of methanol and 1 ml of water.  It is then concentrated in vacuo, diluted with 20 ml of brine, extracted several times with methylene chloride, dried over magnesium sulfate, and evaporated in vacuo.  The residue is purified by chromatography on 15 g of silica gel with chloroform containing 1-10% isopropanol to obtain 295 mg of the desired compound as an oil.  IR, cm-: 3600, 3400, 2945, 1705, 976.  Example 46  (IS, 5R, 6R, 7R, 3R) -3- (4-acetylcarbamoyl-1-butSH1) -6- (E) - (3S) -3-hydroxy-7-methyl-1, 6-octane-1- silt -7-hydroxy-2-oxycacyclo 3. 3 0 octane.  | In a sample of Example 45, out of 200 mg of the carboxylic acid obtained in Example 6 of Example 6, 120 mg of the title compound are obtained as an oil.  IR, see -: 3600, 3380, 2950, 1710, 978.  PRI me R 47.  (IS, 5R, 6R, 7R, 3R) -3- (4-acetylcarbamoyl1-1-butyl) -6- (E) - (38, 4RS) -3-hydroxy-4-metu1-1-octene-6- insh -2-oxabicyclo 3. 3 0 octane. Analogously to example 45, from 200 mg of carboxylic acid obtained in example 18, 135 mg of the desired compound are obtained in the form of an oil, IR, cm-: 3600, 3400, 2945, 1708, 978.  Example 48.  (18, 5R, 6R, 7R, 3R) -3- (4-acetylcarbamoyl-1-butyl) -6- (E) - (3S, 4RS) -4, 7-dimethyl-3-hydroxy-1,6- Octadien-1-yl-7-hydroxy-2-oxabicyclo 3. 3 0 octane.  Analogously to example 45, out of 200 mg of the carboxylic acid obtained in Example 22, 133 mg of the desired compound are obtained in the form of an oil.  IR, cm-: 3600, 3400, 2955, 1710, 978, Example 49.  (IS, 5R, 6R, 7R, 3R) -3- (4-acetylcarbamoyl-1-butyl) -6- (E) (3 R) -4,4-dimethyl-3-hydroxy-1-octene-6- inyl-7-hydroxy 2-oxabicyclo 13. 3 0 octane.  Analogously to example 45, out of 200 mg of the compound that was prepared in Example 26, 120 mg of the target compound were obtained in the form of an oil.   PRI me R 50.  (IS, 5R, 6R, 7R, 3R) -3- (4-acetylcarbamoyl-1-butyl) -6- (E) - (3 R) -3hydroxy-4, 4,7-trimesh1-1,6-octadiene - 1-yl-7-aproxy-1-oxabicyclo 3. 3 0 octane.  Analogously to example 45, out of 200 mg of the carboxylic acid obtained in example 30, 130 mg of the desired compound are obtained in the form of an oil. According to example 45, the carboxylic acids obtained in Examples 4, 8, 10, 12, 14, 16, - 20, 24, 28 and 32 are also converted in acetylcarbamoyl compounds.  PRI me R 51.  (IS, 5R, 6R, 7R, 3R) -3- (4-methoxyncarbenyl-β-butyl) -7-hydroxy-6- (B) - (3R) -3-hydroxy-4,4,7-trimethyl-l, 6-octadien-1-yl -2-oxabicyclo 3. 3 0 octane.  A solution of 100 mg of the carboxylic acid prepared in Example 30 in 10 ml of methylene chloride is mixed dropwise at 0 ° C with an ethereal solution of diazomethane until a yellow color is established.  After 5 min. Evaporated. vacuum, and the residue in a solution of methylene chloride containing 2% isopropanol is filtered through silica gel, to give 95 mg of the title compound as an oil.  IR, see .  3600, 3420, 2955, 1735, 978.  Similarly, they are converted into methyl esters and all other carboxylic acids described in the examples.  .  PRI me R 52.  (IS, 5R, 6R, -7R, 3R) -3- (4-carboxy-1-butyl) -7-g. and iroxy-6- (E) - (3S) -3-hydroxy-1-octene-6-ynyl -2-oxabicyclo 3. 3 0 octane-Tris- (hydroxy-methyl) -amine amino methane.  At a solution of 100 mg of the carboxylic acid obtained in Example 2 in 15 ml of acetonitrile, at 80 ° C, 0.05 ml of a solution of tris (hydroxymethyl) aminomethane prepared by dissolving 82.25-g of base in 150 ml of water is added and settled at room temperature. temperature 16 hours  Filter, wash the precipitate with 5 ml of acetonitrile, dry in vacuo to obtain 80 mg of the title compound as a white powder.  PRI me R 53.  (IS, 5R, 6R, 7R, 3R) -7-hydroxy-6 (E) - (3S) -3-hydroxy-7-methyl-1.6-octadiene-3- (4-methoxycarbon-1-1 - butyl) -2-oxabicyclo 3. 3 0 octane (polar product).  (18, 5R, 6R,, 7R, 38) -7-hydroxy-6- (E) - (38 -3-hydroxy-7-metsh-1.6-octadienyl)) 3- (4-methoxycarbonyl- 1 - butyl) - 2- ok sabicyclo- 3. 3 0 octane (non-polar product).  22 A solution of 480 mg (52, 13E) - (9S, 11R, 15S) -9, 11, 15-trihydroxy-19-methyl-5,13,18-trimethyl methyl ether and 530 mg of mercury (II) acetate 20 ml of tetrahydrofuran is mixed with 200 mg of pulverized calcium carbonate for 48 hours at 25 ° C, then mixed alternately at 0 ° C with 8 ml of 1N.  sodium lye and a solution of 200 mg of sodium borohydride in 8 ml of 1N.  Sodium lye, stirred for 10 minutes, poured from 100 ml of a buffer solution of citrate (pH 4) and extracted three times, respectively, with 50 ml of methylene chloride.  The extract was shaken with a solution of sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo.  On a thin layer chromatogram in the ether / dioxane system (9: 1), the precipitate shows two, non-polar with respect to the starting material, spot.  Silica gel chromatography using hexane / acetic ester is used for purification.  100 mg of the non-polar isomer and 210 mg of the polar isomer are obtained, both as an oil.  IR (polar isomer), 3600, 3450, 2955, 1735 ,.  978.  The infrared spectrum of the non-polar product is identical to the polar one.  Formula of the invention. A method of obtaining irostane derivatives of the general formula I W-CCH2HC hydroxyl or alkoxy group with 1-4 carbon atoms, a lower alkylsulfonylamino group or a lower acyl-: amino group; hydroxymethylene group or group Cn Rj - hydroxyl or acyloxy group with 1--4 carbon atoms; RS 41 Rs f 6 and RV are hydrogen or alkyl with 1-4 carbon atoms, or RS and Re together represent a single bond, or in the case of RI, hydroxyl, i or their salts, characterized in that the compound of the general formula II is dOKi where RI.  ftj, Rj, R4, RS.  Re and R - have the above-mentioned values; they restore alkali metal with borgwdrnd with preliminary, if necessary, protection of free hydroxyl groups and.  the resulting compound is divided into refineries in any sequence, free protected hydroxyl groups are released and / or free goroxyl groups are esterified, the sterified carboxyl group is washed or esterified by carboxyl group, the carboxylic group is replaced by interaction with a compound of the general formula Rg N C O, where RS is the lower alkyl sulfosulfur or lower acyl, and, in case RI is hydroxyl, the carboxyl group is converted to a salt and the resulting alkali is made.  Sources of information taken into account during the examination 1.  Weigand-Hilgetag.  Experimental methods in organic chemistry.  M. Chemistry 1968
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    同族专利:
    公开号 | 公开日
    GB2001650B|1982-03-03|
    DE2734791C2|1990-09-06|
    ATA551578A|1982-11-15|
    FR2398741B1|1980-10-31|
    SE443978B|1986-03-17|
    LU80043A1|1978-12-12|
    IT7826113D0|1978-07-26|
    IT1097554B|1985-08-31|
    JPS6259700B2|1987-12-12|
    AT371454B|1983-06-27|
    IL55236D0|1978-09-29|
    IL55236A|1982-09-30|
    IE781538L|1979-01-29|
    NL7806861A|1979-01-31|
    BE869372A|1979-01-29|
    CA1180700A|1985-01-08|
    CH636354A5|1983-05-31|
    DD138904A5|1979-11-28|
    DK149954C|1987-06-15|
    GR72256B|1983-10-06|
    US4191694A|1980-03-04|
    JPS5427556A|1979-03-01|
    ES472099A1|1979-03-16|
    YU41595B|1987-10-31|
    DE2734791A1|1979-02-15|
    DK336878A|1979-01-30|
    DK149954B|1986-11-03|
    HU179346B|1982-10-28|
    FR2398741A1|1979-02-23|
    AU3843978A|1980-01-31|
    SE7808184L|1979-01-30|
    GB2001650A|1979-02-07|
    AU523593B2|1982-08-05|
    CS207640B2|1981-08-31|
    YU176278A|1983-01-21|
    ZA784307B|1979-07-25|
    NZ187849A|1981-01-23|
    IE47304B1|1984-02-22|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE2734791A|DE2734791C2|1977-07-29|1977-07-29|
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